PROJECT SUMMARY Physiological constraint is a ubiquitous property of life. Constraints arise because organisms are complex and need to simultaneously execute many physiological processes, often with limited resources that can be acquired from the environment. The idea of competition among physiological processes underlies the concept of life history tradeoffs, but only rarely is the mechanistic basis for life history constraint understood. The proposed work is continuation of an ongoing project to study the genetic basis for variation in resistance to bacterial infection, the mechanistic basis for genotype- by-environment interactions in immunity, and the life history tradeoff between immune function and reproductive fitness in the model insect Drosophila melanogaster. The proposed project has two Aims. The specific objectives of the first Aim are to determine how dietary nutrition impacts resistance to infection through consequences on host and microbial physiology, and how genetic variation in both host and pathogen may determine the impact of dietary environment on infection outcome. The objectives of the second Aim are to understand how endocrine signaling that promotes reproductive investment simultaneously limits immune performance, to test the costliness of reproductive investment as a constraint on immunity, and to determine whether infectious pathogens can commandeer nutrients intended for the developing oocyte and use them to promote infectivity. The ultimate of objective of this work is to develop a synthetic model of host immunity that can integrate host and pathogen genetic variation, life history constraint and competing physiology, and environmental variability to predict the outcome of infection.